FDA flags antimicrobial resistance concerns before Iterum's UTI treatment advisory committee

The FDA has expressed concerns about the potential "inappropriate use" of Iterum's oral candidate for uncomplicated urinary tract infections (uUTIs) ahead of an upcoming advisory committee meeting. Iterum's oral sulopenem (sulopenem etzadroxil/probenecid) aims to be the first oral antibacterial of the "penem" class available in the US market. This drug was previously rejected by the FDA in 2021 due to a "lack of substantial evidence of effectiveness." However, Iterum has presented new data, asserting that the drug is a "safe and well-tolerated" oral option suitable for outpatient settings.

Currently, there are several antibacterials available for uUTIs, but side effects and increasing antimicrobial resistance limit their effectiveness for some patients. Carbapenem drugs are often the preferred treatment for patients producing enzymes called extended-spectrum β-lactamases, which are resistant to first-line antibacterials. However, these drugs are administered intravenously and often require hospitalization. An oral alternative like sulopenem would address this unmet need, regulators noted in briefing documents released Thursday. Despite this potential, there are concerns about the appropriate use of the treatment.

The FDA highlighted that inappropriate use of the drug could contribute to antimicrobial resistance (AMR) or increase cross-resistance to other carbapenems. Experts predict that by 2050, AMR could result in 10 million deaths annually. Additionally, regulators are worried about the off-label use of the drug as a step-down treatment following intravenous treatment for complicated UTIs with other drugs. There is no data demonstrating the effectiveness of oral sulopenem as a step-down therapy after IV treatment for complicated UTIs with another β-lactam or carbapenem drug. Regulators suggested that "antimicrobial stewardship and consideration by guidelines committees" may help determine the suitability of sulopenem as a treatment option.

Sulopenem's initial FDA submission was based on data from a Phase 3 trial known as 301. This trial indicated that the drug was superior to an oral comparator, ciprofloxacin, in patients with ciprofloxacin-resistant baseline pathogens but was inferior in patients with ciprofloxacin-susceptible baseline pathogens. As a result, the FDA requested an additional trial.

Iterum's recent refiling included data from a Phase 3 trial known as 310. This trial demonstrated that sulopenem was superior to an oral amoxicillin/clavulanate regimen in terms of overall clinical and microbiological response. However, regulators pointed out that the two Phase 3 trials were not designed to evaluate the efficacy of the drug for treating uUTI caused by resistant bacterial isolates or for uUTI patients who failed first-line treatment.

The FDA is expected to decide on the drug's approval by October 25. According to the draft agenda, the agency’s Antimicrobial Drugs Advisory Committee will not vote on whether to approve the drug. Instead, the committee is asked to discuss the benefits and risks of sulopenem in adults with uUTI caused by designated susceptible microorganisms. They will also consider information that medical providers need to ensure the drug's appropriate use.

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